CN109651371B - Preparation method of valaciclovir hydrochloride - Google Patents
Preparation method of valaciclovir hydrochloride Download PDFInfo
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- CN109651371B CN109651371B CN201811650275.4A CN201811650275A CN109651371B CN 109651371 B CN109651371 B CN 109651371B CN 201811650275 A CN201811650275 A CN 201811650275A CN 109651371 B CN109651371 B CN 109651371B
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- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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Abstract
The invention relates to a preparation method of valaciclovir hydrochloride. The method comprises the following specific steps: 1) synthesis of CBZ-L-valine-acyclovir: sequentially adding N, N-dimethylformamide, N-benzyloxycarbonyl acyl-L-valine, 4-dimethylaminopyridine and acyclovir into a reaction bottle, stirring, cooling, adding an N, N-dimethylformamide solution of a coupling agent, reacting for 2 hours after 1 hour, then heating to 5-15 ℃ for reaction for 21 hours, supplementing N-benzyloxycarbonyl acyl-L-valine, 4-dimethylaminopyridine and N, N-dicyclohexylcarbodiimide, controlling the temperature to 10 ℃, continuing to react for 6 hours, filtering, washing and drying to obtain CBZ-L-valine-acyclovir; 2) synthesizing valaciclovir hydrochloride; 3) and (4) refining valacyclovir hydrochloride. Compared with the prior art, the method has the advantages of mild reaction, convenient operation and environmental protection, and the quality of the produced product reaches the latest standard of pharmacopoeia, thus being suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of valacyclovir hydrochloride.
Background
Valacyclovir hydrochloride is the hydrochloride salt of valacyclovir, which is a precursor of acyclovir-L-valine ester. Acyclovir (Acyclovir) is a synthetic purine nucleoside analogue, has the chemical name of 9- (2-hydroxyethoxymethyl) guanine (CAS number 59277-89-3), is white to faint yellow crystal powder in appearance, and is widely used as a therapeutic drug for herpes, herpes zoster and the like in the world clinically. However, acyclovir is poorly water soluble and poorly absorbed by oral administration (only about 20%), and therefore, in order to maintain effective antiviral blood levels, large doses must be administered orally, thus causing side effects of the drug to be manifested.
US4199574 discloses, first, acyclovir, which has the structural formula shown in formula I:
in order to overcome the defects of acyclovir, amino acid ester of acyclovir, in particular acyclovir-L-valine ester, namely valacyclovir, is rapidly absorbed after being taken orally and is rapidly converted into acyclovir in vivo, the antiviral effect of valacyclovir is exerted, after acyclovir enters herpes infected cells, acyclovir competes with deoxynucleoside for virus thymine kinase or cell kinase, a drug is phosphorylated into activated acyclovir triphosphate, and competes with deoxyguanine triphosphate for virus DNA polymerase as a substrate for virus replication, so that virus DNA synthesis is inhibited, and the antiviral effect is shown.
GLaxo, first marketed as acyclovir prodrug as VALTREX under the trade name VALTREX, valacyclovir hydrochloride in chinese, under the chemical name 1-L-valine-2- [ (6-oxo-2-amino-1, 6-dihydro-9H-purin-9-yl) -methoxy ] ethyl ester hydrochloride. English name: 2- [ (2-Amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy ] ethyl L-Valinate hydrochloride, CAS registry number 124832-26-4, having the formula II:
US4957924 discloses a synthetic route for valacyclovir hydrochloride, i.e. obtaining benzyloxycarbonyl (Cbz) -L-valine-acyclovir by condensation by a conventional method, then removing a protecting group by catalytic hydrogenation, and then acidifying to obtain valacyclovir hydrochloride, wherein the reaction is as follows:
the method in the patent is not suitable for industrial mass production because it requires the use of hydrogen and special equipment (such as an autoclave).
CN1903854A also discloses a method for synthesizing valacyclovir hydrochloride, which comprises the steps of subjecting amino-protected L-valine-acyclovir to hydrogenation reduction reaction in a solvent containing formic acid or formate under the action of a Pd/C catalyst, and obtaining valacyclovir hydrochloride by acidification with hydrochloric acid after the reaction, wherein the reaction is as follows:
the CN1612878A patent discloses a method of deprotecting L-valine-acyclovir protected with t-butyloxycarbonyl in an aqueous solution with concentrated hydrochloric acid, then adding isopropanol to precipitate valacyclovir hydrochloride, and the reaction is as follows:
disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of valacyclovir hydrochloride, which is simple to operate, high in product purity and high in yield.
The invention relates to a preparation method of valaciclovir hydrochloride, which comprises the following specific steps:
1) synthesis of CBZ-L-valine-acyclovir: sequentially adding N, N-dimethylformamide, N-benzyloxycarbonyl acyl-L-valine, 4-dimethylaminopyridine and acyclovir into a 200ml reaction bottle, stirring, cooling to 5 ℃, adding an N, N-dimethylformamide solution of a coupling agent carbodiimide, reacting for 2 hours after 1 hour, then heating to 5-15 ℃, reacting for 21 hours, supplementing N-benzyloxycarbonyl acyl-L-valine, 4-dimethylaminopyridine and N, N-dicyclohexylcarbodiimide, controlling the temperature to 10 ℃, continuing to react for 6 hours, filtering, washing and drying to obtain CBZ-L-valine-acyclovir;
2) synthesis of valacyclovir hydrochloride: opening nitrogen protection, sequentially adding methanol, CBZ-L-valine-acyclovir into a 200ml reaction bottle, adding purified water and methanol into palladium-carbon, uniformly mixing, then adding the mixture into the reaction bottle, heating to 20 ℃, adding formic acid, continuously heating to 40 ℃, reacting for 2 hours, then adding an alcoholic solution of hydrochloric acid, stirring at the temperature of 40 ℃, cooling to 20 ℃, stirring for 10 hours, filtering, transferring the filtrate into a 500ml reaction bottle, slowly adding acetone, cooling to 10 ℃, stirring, crystallizing for 4 hours, filtering, washing and drying to obtain valacyclovir hydrochloride;
3) refining valaciclovir hydrochloride: and sequentially adding methanol and a valacyclovir hydrochloride crude product into a 200ml reaction bottle, heating to 35 ℃, stirring for 1h, then slowly adding acetone, heating to 40 ℃, stirring for 2h, cooling to 10 ℃, stirring for 10h, filtering, washing and drying to obtain valacyclovir hydrochloride.
In the preparation method of valacyclovir hydrochloride, the addition amount of the N-benzyloxycarbonyl acyl-L-valine and the 4-dimethylaminopyridine in the step 1) is added twice, wherein the addition amount is 90-95% of the total amount, and then the rest amount is added.
In the preparation method of valacyclovir hydrochloride, the coupling agent used in the step 1) is N, N-dicyclohexylcarbodiimide.
According to the preparation method of valacyclovir hydrochloride, the mass ratio of the concentrated hydrochloric acid to the alcohol in the step 2) is 1: 10-14.
In the preparation method of valacyclovir hydrochloride, alcohol in the step 2) is methanol.
According to the preparation method of valacyclovir hydrochloride, the mass ratio of the methanol to the valacyclovir hydrochloride crude product in the step 3) is 4-6: 1.
Compared with the prior art, the preparation method of valacyclovir hydrochloride has mild reaction, convenient operation and environmental protection, and the quality of the produced product reaches the latest standard of pharmacopoeia, thus being suitable for industrial production.
Detailed Description
The preparation of valacyclovir hydrochloride according to the present invention is further illustrated by the following specific examples, which should not be construed as limiting the scope of the invention.
Example 1
Synthetic route of valaciclovir hydrochloride
1) Synthesizing CBZ-L-valine-acyclovir;
44.8g of N, N-dimethylformamide, 7.7g of N-benzyloxycarbonyl-L-valine, 0.43g of 4-dimethylaminopyridine and 5.6g of acyclovir are sequentially added into a 200ml reaction bottle, stirred and cooled to 5 ℃, then 23.1g of N, N-dimethylformamide solution of N, N-dicyclohexylcarbodiimide is added, and the addition is completed within 1 hour. And reacting for 2 h. Then the temperature is raised to 10 ℃ for reaction for 21 h. Adding 0.78g of N-carbobenzoxy-L-valine, 0.045g of 4-dimethylaminopyridine and 1.02g of N, N-dicyclohexyl carbodiimide, controlling the temperature to be 10 ℃, and continuing the reaction for 6 hours. Filtering, washing and drying to obtain 10.0g of CBZ-L-valine-acyclovir with the yield of 88 percent.
2) Synthesis of valacyclovir hydrochloride:
starting nitrogen protection, adding 39.0g of methanol and 10.0g of CBZ-L-valine-acyclovir into a 200ml reaction bottle in sequence, adding 4.0g of purified water and 1.0g of methanol into 1.0g of palladium-carbon, uniformly mixing, then adding the mixture into the reaction bottle, heating to 20 ℃, and adding 1.5 g of formic acid. The temperature is increased to 40 ℃ and the reaction is carried out for 2 h. Then 32.1g of methanol solution of hydrochloric acid is added, the temperature is controlled to be 40 ℃, the mixture is stirred, the temperature is reduced to 20 ℃, the mixture is stirred for 10 hours, the mixture is filtered, the filtrate is transferred to a 500ml reaction bottle, 117.5g of acetone is slowly added, the temperature is reduced to 10 ℃, the mixture is stirred and crystallized for 4 hours, and the mixture is filtered, washed and dried to obtain 7.0g of valacyclovir hydrochloride with the yield of 89 percent.
3) Refining valaciclovir hydrochloride:
42.0g of methanol and 7.0g of valacyclovir hydrochloride crude product are sequentially added into a 200ml reaction bottle, the temperature is increased to 35 ℃, the stirring is carried out for 1h, then 66.2g of acetone is slowly added, the temperature is increased to 40 ℃, the stirring is carried out for 2h, the mixture is cooled to 10 ℃, and the stirring is carried out for 10 h. Filtering, washing and drying to obtain 6.0g valaciclovir hydrochloride with the yield of 86%.
Example 2
1) Synthesis of CBZ-L-valine-acyclovir, the same as in example 1. 2) Valacyclovir hydrochloride was synthesized as in example 1.
3) Refining valaciclovir hydrochloride:
adding 42.0g of methanol and 7.0g of valacyclovir hydrochloride crude product into a 200ml reaction bottle in sequence, heating to 35 ℃, stirring for 1h, then slowly adding 66.2g of acetone and 11.2g of naked-capsule lignan, heating to 40 ℃, stirring for 2h, cooling to 10 ℃, and stirring for 10 h. Filtering, washing and drying to obtain 5.2g valaciclovir hydrochloride with the yield of 75 percent.
Example 3
1) Synthesis of CBZ-L-valine-acyclovir, the same as in example 1. 2) Valacyclovir hydrochloride was synthesized as in example 1.
3) Refining valaciclovir hydrochloride:
adding 42.0g of methanol and 7.0g of valacyclovir hydrochloride crude product into a 200ml reaction bottle in sequence, heating to 35 ℃, stirring for 1h, then slowly adding 66.2g of acetone and X21.2g of nude capsule lignan, heating to 40 ℃, stirring for 2h, cooling to 10 ℃, and stirring for 10 h. Filtering, washing and drying to obtain 6.6g valaciclovir hydrochloride with the yield of 94 percent.
Example 4
1) Synthesis of CBZ-L-valine-acyclovir, the same as in example 1. 2) Valacyclovir hydrochloride was synthesized as in example 1.
3) Refining valaciclovir hydrochloride:
adding 42.0g of methanol and 7.0g of valacyclovir hydrochloride crude product into a 200ml reaction bottle in sequence, heating to 35 ℃, stirring for 1h, then slowly adding 66.2g of acetone and 11.2g of nudiflorin, heating to 40 ℃, stirring for 2h, cooling to 10 ℃, and stirring for 10 h. Filtering, washing and drying to obtain 5.5g valaciclovir hydrochloride with the yield of 79 percent.
Claims (6)
1. A preparation method of valacyclovir hydrochloride is characterized by comprising the following specific steps:
1) synthesis of CBZ-L-valine-acyclovir: sequentially adding N, N-dimethylformamide, N-benzyloxycarbonyl acyl-L-valine, 4-dimethylaminopyridine and acyclovir into a 200ml reaction bottle, stirring, cooling to 5 ℃, adding an N, N-dimethylformamide solution of a coupling agent carbodiimide, reacting for 2 hours after 1 hour, then heating to 5-15 ℃, reacting for 21 hours, supplementing N-benzyloxycarbonyl acyl-L-valine, 4-dimethylaminopyridine and N, N-dicyclohexylcarbodiimide, controlling the temperature to 10 ℃, continuing to react for 6 hours, filtering, washing and drying to obtain CBZ-L-valine-acyclovir;
2) synthesis of valacyclovir hydrochloride: opening nitrogen protection, sequentially adding methanol, CBZ-L-valine-acyclovir into a 200ml reaction bottle, adding purified water and methanol into palladium-carbon, uniformly mixing, then adding the mixture into the reaction bottle, heating to 20 ℃, adding formic acid, continuously heating to 40 ℃, reacting for 2 hours, then adding an alcoholic solution of hydrochloric acid, stirring at the temperature of 40 ℃, cooling to 20 ℃, stirring for 10 hours, filtering, transferring the filtrate into a 500ml reaction bottle, slowly adding acetone, cooling to 10 ℃, stirring, crystallizing for 4 hours, filtering, washing and drying to obtain valacyclovir hydrochloride;
3) refining valaciclovir hydrochloride: adding methanol and a valacyclovir hydrochloride crude product into a 200ml reaction bottle in sequence, heating to 35 ℃, stirring for 1h, then slowly adding acetone and nudiflorin X2, heating to 40 ℃, stirring for 2h, cooling to 10 ℃, stirring for 10h, filtering, washing and drying to obtain valacyclovir hydrochloride.
2. The method of claim 1 wherein the amounts of N-benzyloxycarbonyl-L-valine and 4-dimethylaminopyridine added in step 1) are added in two portions, the first 90-95% of the total amount being added, and the remaining amount being added.
3. The method of preparing valacyclovir hydrochloride as claimed in claim 1 wherein the coupling agent used in step 1) is N, N-dicyclohexylcarbodiimide.
4. The preparation method of valacyclovir hydrochloride as claimed in claim 1, wherein the mass ratio of the concentrated hydrochloric acid to the alcohol in step 2) is 1: 10-14.
5. The method of preparing valacyclovir hydrochloride of claim 1 wherein the alcohol of step 2) is methanol.
6. The preparation method of valacyclovir hydrochloride as claimed in claim 1, wherein the mass ratio of the methanol to the crude valacyclovir hydrochloride in the step 3) is 4-6: 1.
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| CN110437231B (en) * | 2019-09-04 | 2022-04-29 | 上药康丽（常州）药业有限公司 | Preparation method of valaciclovir hydrochloride anhydrous crystal form I |
| CN111233865A (en) * | 2020-03-27 | 2020-06-05 | 上药康丽（常州）药业有限公司 | Method for preparing valacyclovir hydrochloride by using microchannel reactor |
| CN114621096A (en) * | 2020-12-11 | 2022-06-14 | 余购粮 | Synthetic method of 3, 5-dimethyl-1, 2-phenylenediamine dihydrochloride |
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| DE69726255T2 (en) * | 1996-01-19 | 2004-08-26 | Glaxo Group Ltd., Greenford | USE OF VALACICLOVIR FOR THE PRODUCTION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF GENITALHERPES BY ADMINISTRIAL DAILY ADMINISTRATION |
| US20070112193A1 (en) * | 2005-11-14 | 2007-05-17 | Khunt Mayur D | Valacyclovir process |
| CN1903854B (en) * | 2006-08-09 | 2012-05-23 | 丽珠医药集团股份有限公司 | Method of synthesizing valaciclovir hydrochloride |
| CN106632335A (en) * | 2016-12-27 | 2017-05-10 | 河南康达制药有限公司 | Preparation method of valaciclovir hydrochloride |
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